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| '''Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)'''
| | ===Human lysosomal beta-hexosaminidase isoform B in complex with (2R,3R,4S,5R)-2-Acetamido-3,4-Dihydroxy-5-Hydroxymethyl-Piperidinium Chloride (GalNAc-isofagomine)=== |
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| ==Overview==
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| In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how alpha and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations).
| | The line below this paragraph, {{ABSTRACT_PUBMED_12662933}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12662933 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12662933}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Family 20 glycosidase]] | | [[Category: Family 20 glycosidase]] |
| [[Category: Homodimer]] | | [[Category: Homodimer]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:47:51 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 02:36:54 2008'' |